CB2 agonism controls pain and subchondral bone degeneration induced by mono-iodoacetate: Implications GPCR functional bias and tolerance development

Mlost, Jakub; Kostrzewa, Magdalena; Borczyk, Małgorzata; Bryk, Marta; Chwastek, Jakub; Korostyński, Michał; Starowicz, Katarzyna

doi:10.1016/j.biopha.2021.111283

Cited by 21 publications

(24 citation statements)

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“…However, these effects may be masked through the activation of various TRP channels by CBD, as shown in the present study. Moreover, some of the CBD effects may also be mediated by CB2, the activation of which has been shown to exert beneficial effects in OA [3]. However, CBD activity toward CB2 is complicated with reports of partial agonism [7] and negative allosteric modulation [21]; thus, the interaction between CBD and CB2 in OA remains to be described as the effects may also be dependent on receptor availability [22].…”

Section: Discussionmentioning

confidence: 99%

“…CBD treatment partially abolished Trpv4 and Trpm8 upregulation in MIA animals, but only cotreatment with the TRP antagonist significantly decreased the expression of all detected TRP channels (Figure 9E-H). Based on our paper reporting molecular changes in the cartilage and subchondral bone following CB2 activation [3], we decided to evaluate CBD's effects on previously described genes. Similar to previous findings, we observed an upregulation of Il6, Ccl2, Fabp3, and Comp but not Ptgs2 and Alox12 (Figure 10A-F • denotes samples in control group; ■ denotes samples in MIA group; ▲ denotes samples in MIA + CBD group; ▼ denotes samples in MIA + CBD + AP-18 followed by HC-067047 group.…”

Section: Establishing Cbd's Molecular Mechanism Of Action Within Cartilage and Subchondral Bone In An Animal Model Of Oamentioning

confidence: 99%

“…Tissue was dissected on Day 28 after MIA administration and 5 h after the last drug administration. We selected half of the dorsal lumbar spinal cord ipsilateral to the damaged knee and the superficial part of the femoral condylar cartilage (~5 mm) for isolation in reference to our previous studies [2,3]. Tissue was harvested and placed on ice in RNAlater and then stored at −80 °C.…”

Section: Rna Preparationmentioning

confidence: 99%

“…To date, numerous studies have revealed beneficial effects of cannabinoids in preclinical models of OA [1]. This pool of studies involves a multitarget approach [2] as well as CB2 agonism, which has been shown to possess not only antinociceptive and anti-inflammatory effects but also the ability to slow OA progression [3].…”

Section: Introductionmentioning

confidence: 99%

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Computational Approach Reveals Pronociceptive Potential of Cannabidiol in Osteoarthritis: Role of Transient Receptor Potential Channels

2021

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Systems pharmacology employs computational and mathematical methods to study the network of interactions a drug may have within complex biological pathways. These tools are well suited for research on multitarget drugs, such as natural compounds, in diseases with complex etiologies, such as osteoarthritis (OA). The present study focuses on cannabidiol (CBD), a non-psychoactive constituent of cannabis, targeting over 60 distinct molecular targets as a potential treatment for OA, a degenerative joint disease leading to chronic pain with a neuropathic component. We successfully identified molecular targets of CBD that were relevant in the context of OA treatment with both beneficial and detrimental effects. Our findings were confirmed by in vivo and molecular studies. A key role of PPARγ in mediating the therapeutic potential of CBD was revealed, whereas upregulation of multiple transient receptor potential channels demasked CBD-induced heat hyperalgesia. Our findings pave the way for novel CBD-based therapy with improved therapeutic potential but also encourage the use of bioinformatic tools to predict the mechanism of action of CBD in different conditions. We have also created an accessible web tool for analogous analysis of CBD pharmacology in the context of any disease of interest and made it publicly available.

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Section: Discussionmentioning

confidence: 99%

Section: Establishing Cbd's Molecular Mechanism Of Action Within Cartilage and Subchondral Bone In An Animal Model Of Oamentioning

confidence: 99%

Section: Rna Preparationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Computational Approach Reveals Pronociceptive Potential of Cannabidiol in Osteoarthritis: Role of Transient Receptor Potential Channels

2021

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“…In behavioral tests, animals were tested prior to MIA injection (day 0); to apply the 3R principle of animal testing, we determined that no healthy group was necessary. Moreover, according to the 3R principle and based on our previous behavioral research were 1 mg (Mlost et al, 2018b;Mugnaini et al, 2020;Mlost et al, 2021) or 3 mg of MIA (Malek et al, 2015;Pajak et al, 2017;Mlost et al, 2018a;Bryk et al, 2020) were successfully used, we decided to examine only 1 and 3 mg MIA doses in behavioral tests to minimize the number of animals exposed to painful procedures.…”

Section: Animalsmentioning

confidence: 99%

Sodium Monoiodoacetate Dose-Dependent Changes in Matrix Metalloproteinases and Inflammatory Components as Prognostic Factors for the Progression of Osteoarthritis

et al. 2021

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Osteoarthritis (OA) is a degenerative joint disease that primarily affects people over 65 years old. During OA progression irreversible cartilage, synovial membrane and subchondral bone degradation is observed, which results in the development of difficult-to-treat chronic pain. One of the most important factors in OA progression is joint inflammation. Both proinflammatory and anti-inflammatory factors, as well as extracellular matrix degradation enzymes (matrix metalloproteinases (MMPs), play an important role in disease development. One of the most widely used animal OA models involves an intra-articular injection of sodium monoiodoacetate (MIA) directly into the joint capsule, which results in glycolysis inhibition in chondrocytes and cartilage degeneration. This model mimics the degenerative changes observed in OA patients. However, the dose of MIA varies in the literature, ranging from 0.5 to 4.8 mg. The aim of our study was to characterize grading changes after injection of 1, 2 or 3 mg of MIA at the behavioral and molecular levels over a 28-day period. In the behavioral studies, MIA injection at all doses resulted in a gradual increase in tactile allodynia and resulted in abnormal weight bearing during free walking sequences. At several days post-OA induction, cartilage, synovial membrane and synovial fluid samples were collected, and qPCR and Western blot analyses were performed. We observed significant dose- and time-dependent changes in both gene expression and protein secretion levels. Inflammatory factors (CCL2, CXCL1, IL-1β, COMP) increased at the beginning of the experiment, indicating a transient inflammatory state connected to the MIA injection and, in more severe OA, also in the advanced stages of the disease. Overall, the results in the 1 mg MIA group were not consistently clear, indicating that the lowest tested dose may not be sufficient to induce long-lasting OA-like changes at the molecular level. In the 2 mg MIA group, significant alterations in the measured factors were observed. In the 3 mg MIA group, MMP-2, MMP-3, MMP-9, and MMP-13 levels showed very strong upregulation, which may cause overly strong reactions in animals. Therefore, a dose of 2 mg appears optimal, as it induces significant but not excessive OA-like changes in a rat model.

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Mit sichtbarem Licht schaltbare Benzimidazol‐Azo‐Arene wirken als β‐Arrestin2 funktionell selektive Cannabinoid‐Rezeptor 2 Agonisten

Steinmüller,

Fender,

Deventer

et al. 2023

Angewandte Chemie

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Der Cannabinoid 2 Rezeptor (CB2R) besitzt großes therapeutisches Potential bei zahlreichen pathophysiologischen Prozessen wie z. B. der Neuroinflammation. Signalweg‐selektive Liganden werden benötigt, um mangelnden klinischen Erfolg zu überwinden und um die Zusammenhänge zwischen einzelnen Signalwegen und deren therapeutischen Effekten zu beleuchten. Hier berichten wir vom Design und der Synthese eines photoschaltbaren chemischen Gerüsts basierend auf der “privilegierten” Struktur des Benzimidazols und seiner Anwendung als funktionell selektiven CB2R “Wirksamkeitsschalter” (”efficacy switch”). Benzimidazol‐Azo‐Arene bieten großes Potential für eine breite Erweiterung der Photopharmakologie auf eine Vielzahl optisch adressierbarer biologischer Zielstrukturen. Wir haben dieses Gerüst verwendet, um Substanz 10 d zu entwickeln, ein “trans‐on” Agonist, der als molekulare Sonde dient, um den β‐Arrestin2 (βArr2) Signalweg am CB2R zu untersuchen. Die selektive Aktivierung des βΑrr2 Signalweges wurde mittels CB2R Internalisierung und βArr2 Rekrutierung nachgewiesen, während keine Aktivierung bei der Betrachtung von Gα16 oder mini‐Gαi auftrat. Insgesamt stellt Substanz 10 d den ersten Licht‐abhängigen funktionell selektiven Agonisten dar, mit dem die komplexen βArr2‐abhängigen Mechanismen der Endozytose am CB2R untersucht werden können.

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CB2 agonism controls pain and subchondral bone degeneration induced by mono-iodoacetate: Implications GPCR functional bias and tolerance development

Cited by 21 publications

References 62 publications

Computational Approach Reveals Pronociceptive Potential of Cannabidiol in Osteoarthritis: Role of Transient Receptor Potential Channels

Computational Approach Reveals Pronociceptive Potential of Cannabidiol in Osteoarthritis: Role of Transient Receptor Potential Channels

Sodium Monoiodoacetate Dose-Dependent Changes in Matrix Metalloproteinases and Inflammatory Components as Prognostic Factors for the Progression of Osteoarthritis

Mit sichtbarem Licht schaltbare Benzimidazol‐Azo‐Arene wirken als β‐Arrestin2 funktionell selektive Cannabinoid‐Rezeptor 2 Agonisten

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